ABSTRACT Multiple neurologic and psychiatric disorders including Parkinson disease (PD), Huntingon disease (HD), dystonia and schizophrenia involve dopaminergic (DA) pathways as part of pathophysiology or treatment. Changes in function of nigrostriatal pathways may reflect either presynaptic or postsynaptic effects. Most previous studies focused on presynaptic changes. This proposal focuses on phosphodiesterases (PDEs) that control signal transduction of both families of DA receptors (D1-like and D2-like). PDE10A, the PDE subtype restricted to striatal medium spiny neurons (MSNs) and is expressed in direct (mosty D1-mediated) and indirect pathway neurons (mostly D2-mediated). PET ligands for PDE10A could facilitate study of pathophysiology, disease progression or target engagement for diseases with striatal pathologies such as PD or HD. However, the interactions among presynaptic nigrostriatal neurons, DA receptors, behavior and PDE10A remain unknown. Failure to understand these relationships led to confusion about interpretation of clinical studies using presynaptic molecular DA biomarkers. Molecular imaging measures also may be altered by either acute or chronic drug exposures, thus investigation of those potential effects also will permit unabmiguous interpretation of human studies. This proposal will help prevent such confusion by directly determining the effects of nigrostriatal injury on striatal PDE10A, comparing with presynaptic measures, D1-like and D2-like DA receptors, other striatal neurotransmitters and motor behavior in nonhuman primates (NHPs). We will leverage previously collected tissues from NHPs that have been treated with varying doses of intracarotid (ic) MPTP that causes graded degrees of nigrostriatal injury. We also will study new NHPs to determine the relationships between in vivo PET measures of PDE10A with other presynaptic and postsynaptic biomarkers. We will use two different PET radioligands for PDE10A that have different tracer kinetic properties. Finally, we will determine the effects of acute or chronic drugs on in vivo PDE10A in striatum since drug effects can be a major confound in human imaging studies, particularly of dopaminergic pathways. These proposed studies will permit unambiguous interpretation of PDE10A PET radioligands to investigate relevant pathophysiologies or provide measures of target engagement of new therapies for PD, HD and possibly psychosis.